Novel acyclic chiral compound from garcinia acid and process for preparing the same

ABSTRACT

The present invention relates to a novel acyclic chiral compound of Garcinia acid of formula I,  
                 
 
     Wherein:  
     R 2 =R 5 =lower aryl ester or alkyl ester or substituted aryl alcohol or alkyl alcohol  
     R 3 =substituted aryl ester or alkyl ester or substituted aryl alcohol  
     R 1 =R 4 =hydroxyl or  
                 
 
     And a process for preparing the same

BACKGROUND OF THE INVENTION

[0001] Garcinia acid [(−)-Hydroxycitric acid lactone or(2S,3S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid] isisolated from the fruits of Garcinia cambogia, Garcinia indica andGarcinia atroviridis. This molecule is widely used as an importantingredient in many pharmaceutical formulations.

[0002] The non-availability of Garcinia acid in the market, in the pureform, has resulted in the limited use of these compounds in the area oforganic synthesis and pharmaceutical front. This is due to the lack ofany commercially viable large-scale manufacturing process. In U.S.patent application Ser. No. 09/365,300 economic, commercially viable,cost effective process for the large-scale isolation of Garcinia acidhas been described.

[0003] The object of the present invention is to prepare hithertounknown acyclic chiral molecules from Garcinia acid.

[0004] To achieve the said objective this invention provides novelchiral derivatives of Garcinia acid of formula I

[0005] wherein:

[0006] R₂=R₅=lower aryl/alkyl ester or substituted aryl/alkyl alcohol

[0007] R₃=substituted aryl/alkyl ester or substituted aryl alcohol

[0008] R₁=R₄=hydroxyl or

[0009] In the above formula I

[0010] R₂ an R₅ is selected from —COOCH₃,—COOC₂H₅, —COOCH(CH₃)₂,—C(Ph)₂OH, —C(4-MePh)₂OH, —C(1-Naphth)₂OH

[0011] R₁ and R₄ is OH or

[0012] R₃ is selected from —CH₂COOCH₃, —CH₂COOC₂H₅, —CH₂COOCH(CH₃)₂,—CH₂C(Ph)₂OH, —CH₂C(4-MePh)₂OH, —CH₂C(1-Naphth)₂OH

[0013] to form various chiral derivatives, namely, chiral triesters,chiral ketals and chiral alcohols.

[0014] Chiral triester derivatives:

[0015] R₂=R₅=—COOCH₃, R₁=R₄=—OH and R₃=—CH₂COOCH₃

[0016] R₂=R₅=—COOC₂H₅; R₁=R₄=—OH; R₃=—CH₂COOC₂H₅

[0017] R₂=R₅=—COOCH(CH₃)₂; R₁=R₄=—OH; R₃=—CH₂COOCH(CH₃)₂

[0018] Chiral ketal derivatives:

[0019] Chiral alcohol derivatives (diols):

Summary of the Chiral Derivatives of Garcinia acid is Given Below inScheme I

[0020]

[0021] The present invention further provides a process for preparingthe chiral triester derivatives of formulae comprising:

[0022] refluxing garcinia acid with appropriate alcohol in presence ofan inorganic catalyst for 6-12 hours,

[0023] adjusting the pH of the reaction-mixture using aqueous alkalisolution,

[0024] concentrating the said reaction-mixture by evaporation,extracting the said concentrate with an organic solvent,

[0025] The said appropriate alcohols are selected from methanol, ethanoland isopropanol.

[0026] The said catalyst is conc.HCl.

[0027] The said organic solvent is chloroform.

[0028] The present invention further includes a process for preparingthe chiral alcohol derivatives of formulae If to Ih comprising:

[0029] adding solution of chiral acetal/ketal in an organic solvent to asolution of appropriate grignard reagent(ArMgX) in an organic solvent,

[0030] refluxing the mixture for 10-20 hours,

[0031] adding the inorganic salt solution to the chilled reactionmixture,

[0032] collecting the organic phase and extracting the aqueous layerfurther with an organic acid,

[0033] drying the organic extract using an inorganic salt,

[0034] evaporating the said extract,

[0035] subjecting the residue to chromatography.

[0036] The organic solvent is tetra hydro furan (THF).

[0037] The said appropriate grignard reagent is phenyl Mg bromide,methylphenyl Mg bromide, naphthyl Mg bromide.

[0038] The said inorganic salt is ammonium chloride and organic solventused for extraction is ether.

[0039] The salt used for drying the extract is sodium sulphate.

[0040] The chromatography employed for purification is columnchromatography.

[0041] The gel used for chromatography is silica gel.

[0042] The eluant used for chromatography is hexane-chloroform mixture.

[0043] Chiral ketals were prepared using standard procedures.

[0044] The invention will now be described with reference to thefollowing examples:

[0045] Chiral triester derivatives:

EXAMPLE 1 Trimethyl (1S,2S)-1,2-dihydroxy-1,2,3-propanetricarboxylate(Ia)

[0046] Garcinia acid (5.0 g, 26.3 mmol) was refluxed with methanol (100ml) and conc. HCl (3 ml) for 12 hours. pH of the reaction mixture wasadjusted to neutral using aqueous solution of sodium bicarbonate. Theresultant solution was evaporated and extracted with chloroform (4×50ml). The combined chloroform extracts was dried (sodium sulphate) and onconcentration furnished Ia.

[0047] Yield: 2.0 g (30%)

EXAMPLE 2 Triethyl (1S,2S)-1,2-dihydroxy-1,2,3-propanetricarboxylate(Ib)

[0048] Ib was prepared from Garcinia acid and ethanol in 46% yield bythe same procedure used to prepare Ia from Garcinia acid.

EXAMPLE 3 Triisopropyl (1S,2S)-1,2-dihydroxy-1,2,3-propanetricarboxylate(Ic)

[0049] Ic was prepared from Garcinia acid and dry isopropanol by thesame procedure used to prepare Ia from Garcinia acid.

[0050] Melting point: 128° C.

[0051] Yield 4.0 g (66%)

EXAMPLE 4Dimethyl(4S,5S)-2,2-dimethyl-4-(2-oxo-2-methoxyethyl)-1,3-dioxolane-4,5-dicarboxylate(Id)

[0052] To Ia (2.0 g, 8 mmol) in dry acetone (50 ml), anhydrous coppersulphate (1.0 g) and a few drops of conc. sulphuric acid were added. Themixture was refluxed for four hours, followed by filtration andneutralisation using aqueous sodium bicarbonate solution. The resultantsolution obtained after evaporation was extracted with hexane (4×25 ml).The combined extracts after washing with water (50 ml) was dried withsodium sulphate. Upon evaporation, Id obtained as an yellow oil.

[0053] Yield: 0.5 g (22%)

EXAMPLE 5 Diethyl(4S,5S)-2,2-dimethyl-4-(2-oxo-2-ethoxyethyl)-1,3-dioxolane-4,5-dicarboxylate(Ie)

[0054] Ie was prepared from Ib in 44% yield by the same procedure usedto prepare Id from Ia.

EXAMPLE 6 (4S,5S)-4-(2-hydroxy-2,2-diphenylethyl)-2,2-dimethyl-alpha,alpha,alpha′,alpha′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (If)

[0055] A solution of Id (1 g, 3.4 mmol, in 7 ml THF) was added to asolution of Phenyl magnesium bromide in THF (20 ml, 1M) and the mixturewas refluxed for 15 hours. To the chilled reaction mixture aqueousammonium chloride solution (20 ml) was added. The organic phase wascollected and the aqueous layer was extracted with ether (5×10 ml). Thecombined organic phase was dried (sodium sulphate). The solution uponevaporation followed by column chromatography (silica gel 60-120 mesh,eluent: hexane) yielded If.

[0056] Yield: 1.0%

USES

[0057] pharmaceutical applications

[0058] chiral derivatives Ia-Ic and If-Ih is used for the preparation ofchiral catalyst and chiral auxiliaries.

[0059] The derivatives of Ia-Ih is used as chiral synthons

We claim:
 1. A novel acyclic chiral compound of Garcinia acid of formulaI,

Wherein: R₂=R₅=lower aryl ester or alkyl ester or substituted arylalcohol or alkyl alcohol R₃=substituted aryl ester or alkyl ester orsubstituted aryl alcohol R₁=R₄=hydroxyl or


2. A compound as claimed in claim 1 wherein, R₂ and R₅ is selected from—COOCH₃, —COOC₂H₅, —COOCH(CH₃)₂, —C(Ph)₂OH, —C(4-MePh)₂OH,—C(1-Naphth)₂OH R₁ and R₄ is OH or

R₃ is selected from —CH₂COOCH₃, —CH₂COOC₂H₅, —CH₂COOCH(CH₃)₂,—CH₂C(Ph)₂OH, —CH₂C(4-MePh)₂OH, —CH₂C(1-Naphth)₂OH.
 3. A compound asclaimed in claim 2 wherein, R₂=R₅ —COOCH₃, R₁=R₄=—OH and R₃=—CH₂COOCH₃and said compound is Trimethyl(1S,2S)-1,2-dihydroxy-1,2,3-propanetricarboxylate


4. A compound as claimed in claim 2 wherein, R₂=R₅=—COOC₂H₅; R₁=R₄=—OH;R₃=—CH₂COOC₂H₅ and said compound is Triethyl(1S,2S)-1,2-dihydroxy-1,2,3-propanetricarboxylate


5. A compound as claimed in claim 2 wherein, R₂=R₅=—COOCH(CH₃)₂;R₁=R₄=—OH; R₃=—CH₂COOCH(CH₃)₂ and said compound isTriisopropyl(1S,2S)-1,2-dihydroxy-1,2,3-propanetricarboxylate


6. A compound as claimed in claim 2 wherein

R₂=R₅=—COOCH₃; R₃=—CH₂COOC₂H₅ and said compound isDimethyl(4S,5S)-2,2-dimethyl-4-(2-oxo-2-methoxyethyl)-1,3-dioxolane-4,5-dicarboxylate


7. A compound as claimed in claim 2 wherein

—COOC₂H₅; R₃=—CH₂COOC₂H₅ and said compound is Diethyl(4S,5S)-2,2-dimethyl-4-(2-oxo-2-ethoxyethyl)-1,3-dioxolane-4,5-dicarboxylate


8. A compound as claimed in claim 2 wherein

R₂=R₅=—C(Ph)₂OH; R₃=—CH₂C(Ph)₂OH and said compound is(4S,5S)-4-(2-hydroxy-2,2-diphenylethyl)-2,2-dimethyl-alpha,alpha,alpha′,alpha′-tetraphenyl-1,3-dioxolane-4,5-dimethanol


9. A compound as claimed in claim 2 wherein,

R₂=R₅=—C(4-MePh)₂OH; R₃=—CH₂C(4-MePh)₂OH


10. A compound as claimed in claim 2 wherein

R₁=R₅=—C(1-Naphth)₂OH; R₃=—CH₂C(1-Naphth)₂OH


11. A process for preparing the chiral triesters derivatives of formulaeIa to Ic as claimed in claims 1 comprising refluxing garcinia acid withappropriate alcohol in presence of an inorganic catalyst for 6-12 hours,adjusting the pH of the reaction-mixture using aqueous alkali solution,concentrating the said reaction-mixture by evaporation, extracting thesaid concentrate with an organic solvent.
 12. A process as claimed inclaim 11 wherein, the said appropriate alcohols is selected frommethanol, ethanol and isopropanol.
 13. A process as claimed in claim 11wherein, the said catalyst is concentrated HCl.
 14. A process as claimedin claim 11 wherein, the said organic solvent is chloroform.
 15. Aprocess for preparing the chiral alcohols of formula If to Ih as claimedin claim 1 comprising: adding solution of chiral acetal or ketal in anorganic solvent to a solution of appropriate grignard reagent(ArMgX) inan organic solvent, refluxing the mixture for 10-20 hours, adding theinorganic salt solution to the chilled reaction mixture, collecting theorganic phase and extracting the aqueous layer further with an organicacid, drying the organic extract using an inorganic salt, evaporatingthe said extract, subjecting the residue to chromatography.
 16. Aprocess as claimed in claim 15 wherein, the organic solvent is tetrahydrofuran (THF).
 17. A process as claimed in claim 15 wherein, the saidappropriate grignard reagent is phenyl Mg bromide, methylphenyl Mgbromide, naphthyl Mg bromide.
 18. A process as claimed in claim 15wherein, the said inorganic salt is ammonium chloride.
 19. A process asclaimed in claim 15 wherein, the said organic solvent used forextraction is ether.
 20. A process as claimed in claim 15 wherein, thesaid salt used for drying the extract is sodium sulphate.
 21. A processas claimed in claim 15 wherein, the chromatography employed forpurification is column chromatography.
 22. A process as claimed in claim15 wherein, the gel used for chromatography is silica gel.
 23. A processas claimed in claim 15 wherein, the eluant used for chromatography ishexane-chloroform mixture.